Treatment Decisions for Patients with Newly Diagnosed Multiple Myeloma
Abstract & Commentary
By Jerome W. Yates, MD, Hematology/Immunology Unit, National Institute on Aging, NIH. Dr. Yates reports no financial relationships relevant to this field of study.
Synopsis: Two very recent publications address the management of newly diagnosed multiple myeloma. In the first, two bortezomib-containing three-drug regimens proved equally effective as a more complex four-drug regimen in achieving meaningful initial responses. The second demonstrated the value of maintenance lenalidomide for achieving longer progression-free survival.
Sources: Kumar S, et al. Randomized, multicenter, phase 2 (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 2012;119:4375-4382.
Palumbo A, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 2012;366:1759-1769.
Over the past 15 years, new drugs, such as the proteasome inhibitor bortezomib and the IMiDs (thalidomide and lenalidomide), have become available for the treatment of myeloma, and when used in combination either together or with established drugs, such as melphalan, cyclophosphamide, doxorubicin and dexamethasone, there has been striking improvement in response rates, progression-free survival, and overall survival.1-3 Yet, there remain a number of questions regarding which drug combinations and what schedules will provide optimal outcomes. The EVOLUTION study, funded by Janssen Global Services and Millennium Pharmaceuticals Inc., was designed to examine various bortezomib combinations including the four-drug combination bortezomib (V), dexamethasone (D), cyclophosphamide (C), lenalidomide (R) [VDCR] compared with two commonly used three-drug regimens (VDR and VDC) as initial treatment.
The EVOLUTION study design included an initial Phase 1 component in which the maximum tolerated dose of cyclophosphamide as a component of the VDCR regimen was determined, and the results had been previously published.4 The current report describes the subsequent randomized Phase 2 trial that evaluated VDC, VDR, and VDCR in previously untreated multiple myeloma (MM). Patients received V 1.3 mg/m2 (days 1, 4, 8, 11) and D 40 mg (days 1, 8, 15), with either C 500 mg/m2 (days 1, 8) and R 15 mg (days 1-14; VDCR), R 25 mg (days 1-14; VDR), C 500 mg/m2 (days 1, 8; VDC) or C 500 mg/m2 (days 1, 8, 15; VDC-mod) in 3-week cycles (maximum eight cycles), followed by maintenance with V 1.3 mg/m2 (days 1, 8, 15, 22) for four 6-week cycles (all arms).
Using the International Myeloma Working Group uniform response criteria, very good partial response was seen in 58%, 51%, 41%, and 53% (complete response rate of 25%, 24%, 22%, and 47%) of patients (VDCR, VDR, VCD, and VCD-mod, respectively); the corresponding 1-year progression-free survival was 86%, 83%, 93%, and 100%, respectively. Common adverse events included hematologic toxicities, peripheral neuropathy, fatigue, and gastrointestinal disturbances.
Whereas a substantial subset of patients (42%) enrolled in the EVOLUTION study went on to receive autologous stem cell transplant (ASCT) after four cycles of treatment, many newly diagnosed myeloma patients are considered ineligible for such an aggressive approach on the basis of comborbidities, functional impairments, or advanced age. In a separate multicenter trial also published this month, Palumbo and colleagues reported on their Celgene-sponsored study in which newly diagnosed MM patients who were not considered eligible for ASCT (on the basis of comorbidities, functional impairments, or advanced age) were randomly assigned to receive nine 4-week cycles of oral melphalan, prednisone, lenalidomide induction followed by lenalidomide maintenance therapy until a relapse or disease progression occurred (MPR-R; n = 152), or to receive MPR (153 patients) or MP (154 patients) without maintenance therapy. The primary endpoint was progression-free survival and this was found to be significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio [HR], 0.49; P < 0.001) or MP (13 months; HR, 0.40; P < 0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs 50% with MP; P < 0.001 and P = 0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65-75 years of age but not in those > 75 years of age (P = 0.001 for treatment-by-age interaction).
The EVOLUTION study demonstrated that bortezomib containing three-drug regimens were highly active and well tolerated in previously untreated MM. Based on their findings, the authors favored VDR or the modified VCD for clinical practice and for further comparative testing. Notably, the four-drug VDCR regimen showed no substantial advantage over the three-drug combinations. For the treatment of patients who might not otherwise be candidates for parenteral therapy, let alone ASCT, the Palumbo report provides direction. As expected, the oral MPR regimen was more effective in terms of response rate when compared to MP, and the addition of maintenance lenalidomide (MPR-R) resulted in remarkably longer progression-free survival. The implications of this important finding were balanced in an accompanying editorial in which concerns were raised about the potential risks of maintenance therapy in terms of second malignancy as well as its impact on quality of life.5 Also, the editorialist raised the question of the relevance of using progression-free survival as the primary endpoint in maintenance trials.
Thus, community oncologists have two new pieces of data to advise regarding initial management of myeloma. Of course, there remain a number of questions, none the least of which is on what basis do we choose whether a patient will be able to tolerate the more aggressive regimens and will maintenance therapy, now known to extend progression-free survival, translate into improved overall survival?
1. Cavo M, et al. Bortezomib with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem cell transplantation in newly diagnosed multiple myeloma: A randomised phase 3 study. Lancet 2010;376:2075-2085.
2. Reeder CB, et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: High response rates in a phase II clinical trial. Leukemia 2009;23:1337-1341.
3. Richardson PG, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010;116:679-686.
4. Kumar SK, et al. Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: Phase 1 results from the multicenter EVOLUTION study. Leukemia 2010;24:1350-1356.
5. Badros AZ. Lenalidomide in myeloma a high-maintenance friend. N Engl J Med 2012;366:1836-1838.